According to the American Heart Association, heart disease, also called cardiovascular disease and coronary heart disease, is a simple term used to describe several problems related to plaque buildup in the walls of the arteries, or atherosclerosis. As the plaque builds up, the arteries narrow, making it more difficult for blood to flow and creating a risk for heart attack or stroke.
Atherosclerosis is a condition of hardening of the arteries, in which plaque builds up inside the arteries. Plaque is made of cholesterol, fatty substances, cellular waste products, calcium and fibrin (a clotting material in the blood). Plaque may partially or totally block the blood's flow through an artery in the heart, brain, pelvis, legs, arms or kidneys. Two things that can happen where plaque occurs include (1) a piece of the plaque may break off; and (2) a blood clot (thrombus) may form on the plaque's surface. Some of the diseases that may develop as a result of atherosclerosis include coronary heart disease, angina (chest pain), carotid artery disease, peripheral artery disease (PAD) and chronic kidney disease.
Arteriosclerosis is a leading cause of death in the Western countries. It is becoming increasingly clear that arteriosclerosis is an immuno-inflammatory process that involves complex interactions between the vessel wall and various blood components. The atherogenic process involves sequestration of partially oxidized lipids in the vessel wall that leads to endothelial injury. Endothelial alteration promotes adherence of mononuclear cells and platelets, which contribute to phenotypic transformation of medial smooth muscle cells from adult to embryonic forms. These transformed muscle cells proliferate and migrate to intima. Simultaneously, accumulation of lipids by monocytes leads to the formation to foam cells. The platelets, macrophages, and proliferating smooth muscle cells of atherosclerotic plaque provide important targets for the development of non-invasive diagnostic agents.
Several imaging modalities and molecular imaging techniques were used to image and characterize plaque. These imaging methods include some advancements in Intravascular ultrasound (IVUS), Optical Coherence Tomography (OCT), CT, near infrared spectroscopy molecular imaging, MR and MR molecular imaging and The standard technique for diagnosis of atherosclerotic lesions utilizes arteriography assessment and development of a non-invasive test is highly desirable. Such a test could be important not only for diagnosis but also for the development and monitoring of therapies directed at altering the natural history of these lesions. However, there are a limited number of reports describing non-invasive visualization of atherosclerotic lesions. These studies have targeted the thrombotic component overlying the atherosclerotic lesion (with radiolabeled fibrinogen), platelet aggregation at regions of turbulent flow (with labeled platelets or platelet-specific antibodies) or proteins likely to be incorporated into atherosclerotic lesions (with radiolabeled autologous lipoproteins). Nonspecific uptake of human IgG via Fc receptors of macrophages has also been used as the basis for a targeting strategy. Other methods developed monoclonal IgM antibody, Z2D3, which was initially developed with specificity for an antigen expressed by the proliferating smooth muscle cells of human atherosclerotic lesion and P2 targeting like Ap4A.
Coronary heart disease alone caused 1 of every 6 deaths in the United States in 2009. Each year, an estimated 635,000 Americans have a new coronary attack and 280,000 have a recurrent attack. It is estimated that an additional 150,000 silent first myocardial infarctions occur each year. Approximately every 34 seconds, 1 American has a coronary event, and approximately every 1 minute, an American will die of one.
The total number of inpatient cardiovascular operations and procedures increased 28%, from 5,939,000 in 2000 to 7,588,000 in 2010 (National Heart, Lung, and Blood Institute computation based on National Center for Health Statistics annual data). The total direct and indirect cost of CVD and stroke in the United States for 2009 is estimated to be $312.6 billion. This figure includes health expenditures (direct costs, which include the cost of physicians and other professionals, hospital services, prescribed medications, home health care, and other medical durables) and lost productivity that results from morbidity and premature mortality (indirect costs).
As one can appreciate, sensitive and specific agents are needed to identify the early stages of plaque and thrombus formation to save lives and reduce burden on the current medical system.
Clinical imaging technology plays a significant role in diagnosis and prognosis of heart diseases. Some of the radiopharmaceutical agents currently used for cardiovascular imaging include nuclides such as 201Tl, 99mTc, 133Xe, 11C, 18F, 82Rb, 13N, and the like; chelates of nuclides; radiolabeled metabolic agents such as 11C-deoxy-D-glucose, 18F-2-fluoro-2-deoxy-D-glucose, [18F], [11C]- and [123I]-β-methyl fatty acid analogs, 13N-ammonia, and the like; infarct avid agents such as 99mTc-tetracycline, 99mTc-pyrophosphate, 203Hg-mercurials, 67Ga-citrate, and the like; and radiolabeled ligands, proteins, peptides, and monoclonal antibodies.
The present invention provides anticoagulants such as dabigatran and their derivatives as novel radiopharmaceutical agents for cardiovascular imaging, diagnosis and treatment.